In recent years, there has been considerable interest in identifying progenitor or stem cells in various tissues and their potential use for tissue repopulation. Using a naturally occurring, unique cell transplantation system for the liver (the DPPIV- mutant Fischer 344 rat), studies in our laboratory have demonstrated that early fetal liver epithelial cells can repopulate up to 10% of the parenchymal mass in normal liver, produce both hepatocytic and bile duct epithelial cell progeny and show continued proliferative activity for up to six months after cell transplantation (properties generally attributed to stem cells). We hypothesize that use of a normal liver-based cell transplantation system, such as the one we have established, is critical in determining the stem cell potential of isolated cells and cell lines and the factors that contribute to their proliferation and differentiation in the liver. Within this context, experiments are proposed: 1) to use cytokines and pharmacological agents to augment proliferation of transplanted fetal hepatic cells in our liver-based cell transplantation model, 2) to study the molecular and cellular characteristics of different populations of proliferating fetal liver epithelial cells after transplantation to define their phenotype, proliferative potential, lineage deriving capacity and ability for self renewal and 3) to determine whether mature hepatocytes can pass from the parenchyma into the biliary compartment and exhibit sufficient plasticity to switch their phenotype and become incorporated into bile ducts, demonstrating that the engraftment site in the liver lobule determines the ultimate fate of transplanted hepatic cells. We will also use a recently established DPPIV -/- mouse model comparable to the rat, but now also immunocompromised (Rag2-/-), to permit repopulation studies with selected transgenic and knockout animals exhibiting modified cell cycle regulation, growth factor enhanced or cytokine dependent proliferation. The overall goal of these studies is to find methods to enhance liver repopulation by transplanted hepatic derived cells that will ultimately lead to clinical application in humans.